Aberrant activation of hepatocyte growth factor (HGF) and its receptor c-Met axis promotes tumor growth. Therefore, many clinical trials have been conducted. A phase 3 trial investigating a monoclonal antibody targeting HGF in combination with fluoropyrimidine-based chemotherapy had to be terminated prematurely; however, the reason behind the failure remains poorly defined. In this study, we investigated the influence of HGF on the antineoplastic effects of 5-fluorouracil (5-FU), a fluoropyrimidine, in HepG2 cells. HGF suppressed the proliferative activity of cells concomitantly treated with 5-FU more robustly as compared to that of cells treated with 5-FU alone, and markedly increased the expression of uridine phosphorylase 1 (UPP1). Intracellular concentration of 5-fluorouridine, an initial anabolite of 5-FU catalyzed by UPP1, was increased by HGF. Interestingly, erlotinib enhanced HGF-induced increase in UPP1 mRNA; in contrast, gefitinib suppressed it. Furthermore, erlotinib suppressed HGF-increased phosphorylation of the epidermal growth factor receptor at the Tyr1173 site involved in downregulation of extracellular signal-regulated kinase (Erk) activation, and enhanced the HGF-increased phosphorylation of Erk. Collectively, these findings suggest that inhibition of the HGF/c-Met axis diminishes the effects of fluoropyrimidine through downregulation of UPP1 expression. Therefore, extreme caution must be exercised in terms of patient safety while offering chemotherapy comprising fluoropyrimidine concomitantly with inhibitors of the HGF/c-Met axis.
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Macau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R ChinaMacau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R China
Guo, Jianru
Chen, QianQian
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Macau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R ChinaMacau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R China
Chen, QianQian
Lam, Christopher Wai Kei
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Macau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R ChinaMacau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R China
Lam, Christopher Wai Kei
Wang, Caiyun
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Macau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R ChinaMacau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R China
Wang, Caiyun
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Wong, Vincent Kam Wai
Xu, Fengguo
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China Pharmaceut Univ, Minist Educ, Key Lab Drug Qual Control & Pharmacovigilance, Nanjing 210009, Jiangsu, Peoples R ChinaMacau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R China
Xu, Fengguo
Jiang, ZhiHong
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Macau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R ChinaMacau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R China
Jiang, ZhiHong
Zhang, Wei
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Macau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R ChinaMacau Univ Sci & Technol, Macau Inst Appl Res Med & Hlth, State Key Lab Qual Res Chinese Med, Taipa, Macau, Peoples R China